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Cancer Cell. 2018 Feb 12;33(2):259-273.e7. doi: 10.1016/j.ccell.2018.01.001. Epub 2018 Feb 2.

RHOA G17V Induces T Follicular Helper Cell Specification and Promotes Lymphomagenesis.

Author information

1
Institute for Cancer Genetics, Columbia University, New York, NY 10032, USA.
2
Department of Adult Hematology, Necker Hospital, Paris 75993, France; INSERM U 1163, CNRS ERL 8254, Institut Imagine, Paris 75015, France; Paris Descartes University, Paris 75006, France.
3
Gustave Roussy, Villejuif 94805, France; INSERM U1170, Villejuif 94805, France; Université Paris-Sud, Orsay 91400, France.
4
Department of Pathology and Cell Biology, Columbia University Medical Center, 1130 St Nicholas Avenue, ICRC-401B, New York, NY 10032, USA.
5
Institute for Cancer Genetics, Columbia University, New York, NY 10032, USA; Department of Pathology and Cell Biology, Columbia University Medical Center, 1130 St Nicholas Avenue, ICRC-401B, New York, NY 10032, USA; Department of Pediatrics, Columbia University Medical Center, New York, NY 10032, USA.
6
Institute for Cancer Genetics, Columbia University, New York, NY 10032, USA; Department of Pathology and Cell Biology, Columbia University Medical Center, 1130 St Nicholas Avenue, ICRC-401B, New York, NY 10032, USA. Electronic address: tp2151@columbia.edu.

Abstract

Angioimmunoblastic T cell lymphoma (AITL) is an aggressive tumor derived from malignant transformation of T follicular helper (Tfh) cells. AITL is characterized by loss-of-function mutations in Ten-Eleven Translocation 2 (TET2) epigenetic tumor suppressor and a highly recurrent mutation (p.Gly17Val) in the RHOA small GTPase. Yet, the specific role of RHOA G17V in AITL remains unknown. Expression of Rhoa G17V in CD4+ T cells induces Tfh cell specification; increased proliferation associated with inducible co-stimulator (ICOS) upregulation and increased phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase signaling. Moreover, RHOA G17V expression together with Tet2 loss resulted in development of AITL in mice. Importantly, Tet2-/-RHOA G17V tumor proliferation in vivo can be inhibited by ICOS/PI3K-specific blockade, supporting a driving role for ICOS signaling in Tfh cell transformation.

KEYWORDS:

ICOS; RHOA G17V; T follicular helper cells; TET2; angioimmunoblastic T cell lymphoma

PMID:
29398449
PMCID:
PMC5811310
DOI:
10.1016/j.ccell.2018.01.001
[Indexed for MEDLINE]
Free PMC Article

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